REVIEW article
Front. Oncol.
Sec. Breast Cancer
Volume 15 - 2025 | doi: 10.3389/fonc.2025.1630464
This article is part of the Research TopicAdvancements in Targeted Neoadjuvant and Adjuvant Therapies for Drug-Resistant Breast CancersView all articles
Immunotherapy Resistance in Triple-Negative Breast Cancer: Molecular Mechanisms, Tumor Microenvironment, and Therapeutic Implications
Provisionally accepted
Zijian Zhou1*
Qin Zhou2*- 1Jiangsu University, Zhenjiang, China
- 2Department of Breast surgery, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, China., Suzhou, China
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Triple-negative breast cancer (TNBC) is a unique subtype of breast cancer characterized by high invasiveness, high metastasis rates, and poor prognosis, making it an important focus within global malignancies. Due to the absence of estrogen receptor, progesterone receptor, and HER2 expression, TNBC presents significant challenges in treatment. Metastatic progression markedly increases treatment complexity, drastically reducing patient survival rates. The metastatic and drug resistance processes of TNBC involve complex, multi-step biological mechanisms regulated through various molecular mechanisms and signaling pathways within and outside tumor cells. In recent years, immunotherapy has brought new hope for TNBC. Compared to other breast cancer subtypes, TNBC demonstrates higher immunogenicity, often accumulating a higher mutational burden that generates more neoantigens, thus typically resulting in a tumor microenvironment (TME) enriched with tumorinfiltrating lymphocytes (TILs). Additionally, PD-L1 expression is significantly higher in TNBC compared to other subtypes, closely correlating with TIL abundance. These characteristics position TNBC as a strong candidate for immune checkpoint inhibitor (ICI) therapy. Clinical trials have demonstrated promising efficacy of ICIs in TNBC, overturning previous beliefs that breast cancer is generally insensitive to immunotherapy. This review summarizes recent advances regarding resistance types, molecular mechanisms, associated genes and pathways, the role of the tumor microenvironment, and clinical strategies related to immunotherapy resistance in the neoadjuvant setting of TNBC, aiming to provide insights and guidance for future research exploration and clinical practice.
Keywords: Triple-negative breast cancer, drug resistance mechanism, Genetic mutations, Signaling Pathways, personalized therapy, Review literature
Received: 17 May 2025; Accepted: 13 Aug 2025.
Copyright: © 2025 Zhou and Zhou. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Zijian Zhou, Jiangsu University, Zhenjiang, China
Qin Zhou, Department of Breast surgery, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, China., Suzhou, China
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.